This invention comprises an improved, more economical process for the synthesis of BMS 180048 and analogs. Importantly, the process can be adapted to large-scale manufacture. BMS 180048 is chemically 4-(5-methoxy-4-pyrimidinyl)-1-[3-[5-[[(methylamino)sulfonyl]methyl]-1H-ind ol-3-yl]propyl]piperazine. Synthesis of BMS 180048 and related compounds has been disclosed by Smith, et al. in U.S. Pat. No. 5,300,506, issued Apr. 5, 1994. BMS 180048 and its analogs are antimigraine agents. Currently, BMS 180048 itself is undergoing clinical trials to establish the safety and efficacy of its use in treating vascular headache in patients.
The demand for drug substance has increased substantially with the advent of clinical testing, and a future need for much larger amounts of BMS 180048 is projected due to its intended commercialization. The prior art processes for preparation of BMS 180048 and its analogs proved to be unsatisfactory for adaption to the larger scale production required to meet these demands for large quantities of the drug. The prior art process utilized for synthesis of BMS 180048 and close analogs is set out in Scheme A.
In Scheme A, R can be hydrogen, lower alkyl or trifluoromethyl and R.sup.1 can be hydrogen, lower alkyl or phenyl-lower alkyl. R.sup.2 and R.sup.3 are independently selected from hydrogen and methyl and R.sup.4 is lower alkyl. The symbol n denotes zero or the integers 1 and 2. For BMS 180048: R is methyl; R.sup.1, R.sup.2, and R.sup.3 are hydrogen; R.sup.4 is methyl and n is 1. The compound Y-X denotes reagents that convert hydroxy groups into leaving groups and could be e.g. HBr, Cl--SO.sub.2 Me, etc. Other designations are standard in organic synthesis and are defined infra.
This prior art process is that disclosed by Smith, et. al. with methods of synthesis for the starting materials also being disclosed, e.g. see Example 5 of U.S. Pat. No. 5,300,506 for preparation of the iodoaniline intermediate (IV). As can be appreciated from examination of Scheme A, the final step comprises the coupling reaction of the indolylalkyl component (XV) with the pyrimidinylpiperazine component (VI). Intermediate (XV) is by far the more precious component. Syntheses of pyrimidinylpiperazines are straightforward (e.g. see Examples 21-24 of U.S. Pat. No. 5,300,506) and are amenable to scale-up. On the other hand, construction of compound (XV) requires several steps from intermediate (IV). A process problem with the coupling of (XV) and (VI) is that if the nucleofuge (leaving group, X), that is selected is very labile, e.g. iodide, a second molecule of (XV) attaches to the pyrimidine ring at the 1-nitrogen position to give a quaternary pyrimidinium salt impurity which occurs in yields on the order of10% or more. Selection of a less labile nucleofuge, e.g. mesylate, results in less efficient coupling with a concomitant reduction in overall process yield.
It is further appreciated by those skilled in process development that many processes, procedures, and/or reactions are not amenable to being carried out on a large scale as is done in a pilot plant or a manufacturing facility. Some examples of situations where scale-up can be problematic may involve the use of hazardous or toxic reagents and/or solvents; highly exothermic reactions; high pressure or high vacuum processes, such as those required for certain high pressure reactions or high vacuum distillations; chromatographic separation and/or purification. Also troublesome are processes exhibiting reduced yield on scale-up and the like. A more recent consideration for large scale operations is the limitations which have been set on certain emissions as well as the disposal of waste products from chemical processing. Processes involving these aspects incur higher levels of cost in production.
The prior art process for preparation of BMS 180048 is not amenable to scale-up for many of the reasons listed above as well as other process problems unique to the actual reactions employed. For example: key intermediates in the prior art process such as (XVI) and (XV) are not crystalline materials, thereby complicating purification and handling procedures; product isolated after deprotection is of low quality and end product is contaminated by residual palladium. The most serious drawback, however, was the actual cost of product produced by adaption of the prior art process for large-scale preparation of BMS 180048. A major objective of the present invention then is to provide a synthetic process whose cost considerations allow its utilization on a large scale to be economical.